Currently, we have little understanding of the etiology of myocardial aging. Rarely, studies in animals and humans have considered aging as an independent process and time as the major cause of the aging myopathy. Only occasionally cardiac aging in humans has been characterized independently from concomitant pathologic states. Aging has been interpreted as a variable, which cooperates with a variety of diseases, to define the old, poorly functional heart. This Program Project Grant (PPG) aims at the: a) Definition of myocardial aging; b) Identification of the determinants of the cardiac senescent phenotype; and c) Recognition whether the aging myopathy conditions health and life span. The major hypothesis to be tested is that aging of cardiac stem cells (CSCs) affects the size and properties of the myocyte, vascular, and fibroblast progeny which, in turn, conditions the structure and function of the heart. Aged CSCs may generate a smaller number of senescent myocytes with defects in electrical and mechanical behavior, and a larger number of fibroblasts which, together, underlie diastolic dysfunction and the old cardiac phenotype. This PPG has five objectives: a) To determine whether the adult heart is a self-autonomous organ regulated by the orderly organization and growth of CSCs; b) To determine whether telomeric shortening in CSCs with aging leads to time-dependent changes in the growth properties of CSCs and characteristics of the differentiated progeny; c) To determine whether old CSCs with short telomeres generate functionally-defective myocytes together with enhanced formation of fibroblasts; d) To determine whether accumulation of fibroblasts and myocytes with impaired contractile performance promotes diastolic dysfunction, typically present in the senescent heart; and e) To determine whether strategies preventing the aging myopathy, or reversing myocardial aging can be developed to extend health and life span in the elderly. The common theme of this PPG is understanding the control of CSC growth and commitment, the etiology of CSC senescence and death, and the impact that old CSCs have on the properties of the differentiated progeny The telomere-telomerase axis is viewed as the key regulator of CSC replication, senescence and death, conditioning myocyte, coronary vasculature, and organ aging. Alterations in the turnover rate of cardiomyocytes, vascular cells, and fibroblasts define the aging myopathy. CSCs with preserved function are present in the old heart, and repopulating protocols with CSCs possessing intact telomeres may replace defective myocytes with new, mechanically efficient cells, and restore the coronary vasculature and microvasculature reversing the senescent phenotype, ultimately, prolonging health and life span of the organ and organism. To fulfill these objectives, the role of CSCs in myocardial aging of small (Projects 1 and 2) and large (Project 3) animals and humans (Project 4) will be investigated in an integrated manner to identify the variables that lead to ventricular dysfunction in the old heart.